Transcript Vlachos – Life with DBA (including iron overload)

Life with DBA
Adrianna Vlachos, MD
The Feinstein Institute for Medical Research
Hofstra North Shore-LIJ School of Medicine
Cohen Children’s Medical Center of New York
Pros and cons of DBA treatments
Pros
Corticosteroids
Chronic Transfusions
Bone marrow
transplant
No risk of iron
overload
First line treatment for
severe anemia under 1y
Can lead to resolution of
anemia
Can improve quality of
life
Cons
Risk of low bone
density
Frequent hospital visits for
transfusions
Risk of Graft versus
Host Disease (GVHD),
and infection
Excess weight gain &
impaired growth
Endocrine complications of
iron overload
Risk of graft rejection
Increased risk of
diabetes (at high
doses)
Side-effects of
immunosuppressive
drugs & radiation
Lessons from thalassemia
Usual progression of
Iron overload

Accumulation of iron
◦ Liver
◦ Endocrine glands
◦ Heart
Skin
◦ Often this is stepwise in thalassemia major
◦ NOT so in DBA – Why??
Iron overload

Eventual fibrosis and organ failure
◦ Heart: cardiomyopathy, conduction disturbances
arrhythmia
◦ Liver: abdominal pain, elevated LFTs, hepatomegaly
fibrosis and cirrhosis
◦ Skin: bronzing and gray pigmentation
◦ Endocrine dysfunction
Liver with iron overload
Normal liver
Iron stain of liver – iron staining in hepatocytes and histiocytes
Trichrome stain of liver – medium magnification to show liver cirrhosis with
fibrosis and nodules in a patient with hepatic iron overload (no iron stain)
Dilated cardiomyopathy with iron overload
Hypertrophic
cardiomyopathy
Iron stain of heart
Pancreas with massive iron overload
Normal pancreas
Hypogonadism
• 30-50% of patients have delayed or absent puberty due to
iron overload

After myeloablative BMT:
◦ Females - ovarian malfunction in ~100%
◦ Males - testicular dysfunction in 0-40%

Screening for pituitary-hypothalamic axis (LH and FSH) and
sex hormones (Testosterone or Estradiol)
Hypogonadism

Reproduction and Infertility
◦ Genitalia: primary hypogonadism
◦ Pituitary gland: gonadotropin insufficiency leading to
secondary hypogonadism
Menarche to Menopause
◦ DBAR Women’s study open to review
 Menarche
 Pregnancy
 Menopause
 Preliminary results
◦ Delayed puberty
◦ Early menopause
◦ ? Infertility issues
Hypothyroidism
Found in 2-20 % of patients with iron overload
 After bone marrow transplant: common


Screening with
◦ Thyroid stimulating hormone (TSH)
◦ Total and free Thyroid hormone (T4)
Adrenal insufficiency




Symptoms may be missed because of their vague
nature.
◦ Dark color of non-sun-exposed areas
◦ Extreme tiredness
◦ Nausea, vomiting, abdominal pain, diarrhea,
constipation
Patients on steroids: considered to have adrenal
insufficiency
8-45% of patients with iron overload can have
biochemical adrenal insufficiency (often partial)
Screening with 8 AM cortisol level, plasma renin
activity, aldosterone, androstenedione and DHEAS levels
Diabetes mellitus

Both corticosteroid therapy and iron overload can lead to:
↓ in insulin secretion and ↓ in insulin sensitivity
Diabetes mellitus



•
9-14% of patients with iron overload
? % of patients on chronic corticosteroids
? after bone marrow transplant
Screening with
• fasting blood glucose
• fructosamine level
• HbA1c is not reliable while on transfusions!!
• oral glucose tolerance test
Growth
Growth
Anemia and ?DBA (RP gene)
Iron overload
Short
stature
Absent/
Abnormal
puberty
Hypothyroidism
Low Growth hormone
Glucocorticoids
Short stature in DBA is multifactorial.
Growth


Short stature reported in ~30-50% of DBA patients
Effect on growth may be due to iron overload or steroids
•
Screening with regular growth monitoring for early detection
and more specific testing to check for endocrine causes.
Bone disorders
Hypogonadism
Iron overload
Osteoporosis
Low Vitamin D &
parathyroid gland
failure
Diabetes mellitus
? Low Growth hormone
Glucocorticoids
Osteoporosis is multifactorial in DBA patients.
Bone disorders

No data yet on bone disorders for DBA patients
◦ With iron overload: ???
◦ On chronic corticosteroids: ????
◦ After bone marrow transplant: ???
•
Screening of calcium, parathyroid hormone, vitamin D and
for other endocrine problems
Perform densitometry or DEXA scan
•
Importance of Chelation
Insulin resistance.
Decreased insulin
secretion.
Impaired glucose
tolerance.
Insulin resistance.
High insulin level.
Normal glucose
tolerance
Insulin
dependent
diabetes
mellitus
Intensive chelation in patients with impaired glucose tolerance can
improve beta-cell function and improve blood glucose values.
Less effective in patients who have developed DM and in improving
insulin resistance.
Treatment for endocrinopathies
Timely diagnosis & treatment can prevent
morbidity and possible mortality associated with
some endocrine conditions.
• If not, will develop long-term adverse effects of
an undiagnosed/ untreated endocrine problem.

*Unpublished data presented at Pediatric Endocrine society meeting at Washington DC, 2013
Endocrine research in DBA
with Drs. Lahoti, Speiser, and Harris
SPECIFIC AIMS:
1. To study the effects of iron overload on the endocrine system
in DBA patients receiving transfusions.
2. To estimate how common endocrinopathies are in the DBA
population and correlate them with measures of iron overload.
3. To compare the presence of endocrine dysfunction in the
chronic transfusion-dependent DBA population with those not
on chronic transfusions.
Eligibility Criteria
Inclusion criteria:
 Age 1-39 years; and
 Diagnosed with DBA and enrolled in DBAR
Exclusion criteria:
 Pregnant; or
 Have received a bone marrow transplant
DBAR Research Study
Goal:
◦ 50 transfusion dependent DBA
◦ 25 steroid dependent and remission DBA

Completed and report to follow